WO2024005905A2 - Petites molécules inhibitrices de la sirtuine et leurs utilisations - Google Patents

Petites molécules inhibitrices de la sirtuine et leurs utilisations Download PDF

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WO2024005905A2
WO2024005905A2 PCT/US2023/020366 US2023020366W WO2024005905A2 WO 2024005905 A2 WO2024005905 A2 WO 2024005905A2 US 2023020366 W US2023020366 W US 2023020366W WO 2024005905 A2 WO2024005905 A2 WO 2024005905A2
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compound
activity
sirt5
sirtuin
cancer
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PCT/US2023/020366
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WO2024005905A3 (fr
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Nouri Neamati
Yanghan LIU
Surinder Kumar
David B. Lombard
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The Regents Of The University Of Michigan
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings

Definitions

  • This invention is in the field of medicinal chemistry.
  • the invention relates to a new class of small-molecules having a 2-hydroxybenzoic acid structure which function as sirtuin (e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7) inhibitors and/or degraders which function as effective therapeutic agents for treating, ameliorating, and preventing disorders associated with sirtuin activity (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer).
  • sirtuin e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7
  • this invention also relates to a new class of proteolysis-targeting chimeras (PROTACs) (as defined herein) which function as sirtuin inhibitors and/or degraders within cancer and/or immune cells.
  • PROTACs proteolysis-targeting chimeras
  • Pharmaceutical compositions comprising said compounds are also within the scope of the present invention.
  • Sirtuins are known as nicotinamide adenine dinucleotide (NAD + )-dependent protein deacylases which are involved in many important biological functions, including the regulation of life span, transcription, DNA repair, protein secretion, and metabolism.
  • NAD + nicotinamide adenine dinucleotide
  • Sirtuin-family proteins are NAD + -dependent protein deacylases regulating metabolism and other diverse aspects of cell biology (Giblin et al., 2014). Three sirtuins (S1RT3, S1RT4, and S1RT5) reside primarily or exclusively in the mitochondrial matrix (Lombard et al., 2012). SIRT5 is an inefficient deacetylase, instead removing succinyl, malonyl, and glutaryl groups from lysines of its target proteins (referred to herein as Ksucc, Kmal, and Kglu, respectively) (Du et al., 2011; Park et al., 2013; Peng et al., 2011; Rardin et al., 2013; Tan et al., 2014).
  • SIRT5 knockout mice are grossly unremarkable, fertile, and healthy until at least 18 months of age (Lombard et al., 2007).
  • Germline SIRT5 KO mice show mild biochemical defects in response to a prolonged 48-hour fast (Nakagawa et al., 2009; Nishida et al., 2015; Randin et al., 2013; Yu et al., 2013), and mild cardiac defects with advancing age (Sadhukhan et al., 2016).
  • SIRT5 KO mice actually show modest protection from the negative consequences of high fat diet (Yu et al., 2013).
  • SIRT5 has been implicated in neoplasia, as both an oncogene and a tumor suppressor, in a context-specific manner (Kumar et al., 2018).
  • SIRT5 promotes folate metabolism via activation of mitochondrial serine hydroxymethyltransferase (SHMT2), facilitating cancer cell growth in vitro and in vivo (Yang et al., 2018).
  • Folate metabolism is a target of several approved chemotherapy drugs, likewise, SIRT5 inhibits pyruvate kinase muscle isozyme 2 (PKM2), resulting in accumulation of glycolytic intermediates, driving xenograft growth (Xiangyun et al., 2017).
  • PLM2 pyruvate kinase muscle isozyme 2
  • SIRT5 promotes entry of glutamine into the TCA cycle by activating glutamate dehydrogenase 1 (GLUD1) (Wang et al., 2018). Additionally, SIRT5 desuccinylates citrate synthase (CS), the rate-limiting enzyme in the TCA cycle, promoting its activity (Ren et al., 2020). CS hypersuccinylation inhibits its function and suppresses colorectal cancer cell proliferation and migration (Ren et al., 2020). In breast cancer, SIRT5 regulates glutamine metabolism by desuccinylating glutaminase (GLS), protecting it from ubiquitin-mediated degradation (Greene et al., 2019).
  • GLS glutaminase
  • SIRT5 is required to maintain histone acetylation and methylation to promote expression of key genes, including MITF, a lineage- specific oncogene, and c-MYC (Giblin et al., 2021).
  • MITF a lineage- specific oncogene
  • c-MYC a lineage- specific oncogene
  • recent studies have documented oncogenic roles for SIRT5 in breast cancer and in AML (Yan et al., 2021; Abril et al., 2021).
  • SIRT5 maintains fatty acid oxidation and redox homeostasis by inhibiting dimerization of acyl-CoA oxidase 1 (ACOX1), attenuating its function (Chen et al., 2018). Consistently, in hepatocellular carcinoma, low SIRT5 expression is associated with increased ACOX1 succinylation and activity (Chen et al., 2018).
  • ACOX1 acyl-CoA oxidase 1
  • isocitrate dehydrogenase (IDH) gain-of-function mutants convert a-ketoglutarale (a-KG) into the oncometabolite R-2-hydroxyglutarate (R- 2HG), which in turn inhibits a-KG-dependent enzymes, including DNA and histone demethylases, thereby inducing epigenetic dysregulation (Kumar et al., 2018).
  • Ectopic expression of SIRT5 reverses R-2HG-induced resistance to apoptosis in IDH1 mutant glioma cells, impairing their growth (Li et al., 2015).
  • Hu and colleagues characterized a novel tumor suppressor function of SIRT5 in PDAC (Hu et al., 2021).
  • PROTACs Proteolysis targeting chimeras
  • One ligand can recruit an E3 ubiquitin ligase while the other ligand specifically recruits the protein of interest (Pol).
  • Pol protein of interest
  • PROTACs can recruit the E3 ligase to Pol in a spatially favorable presentation for substrate poly-ubiquitination, leading to subsequent degradation of Pol by the proteasome.
  • occupancy-based pharmacology PROTACs technology offers several advantages. For example, it needs lower concentration than those occupancy-based inhibitors to achieve equivalent therapeutic effects.
  • PROTACs can be used as a novel approach to target so called “undruggable” proteins, such as transcription factors, scaffolding proteins, and non-enzymatic proteins (Toure and Crews, 2016).
  • SIRT5 is a new target for cancer therapy.
  • SIRT5 inhibitors or degrades can be used as a single agent and in combination to treat various cancers as well as other diseases related to SIRT5 dysregulation.
  • New compounds capable of inhibiting SIRT5 activity or degrading SIRT5 are needed.
  • the present invention address this need.
  • the present invention provides a new class of small-molecules having a 2-hydroxybenzoic acid structure which function as sirtuin (e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7) inhibitors and/or degraders which function as effective therapeutic agents for treating, ameliorating, and preventing disorders associated with sirtuin activity (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer).
  • this invention also relates to a new class of proteolysistargeting chimeras (PROTACs) (as defined herein) which function as sirtuin inhibitors and/or degraders within cancer and/or immune cells.
  • PROTACs proteolysistargeting chimeras
  • Pharmaceutical compositions comprising said compounds are also within the scope of the present invention.
  • Form 3 including pharmaceutically acceptable salts, solvates, PROTACs , and/or prodrags thereof.
  • Formulas (1), (2), and (3) are not limited to a particular chemical moiety for RI, R2, R3, A, B and E.
  • the particular chemical moiety for RI, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin activity (e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7).
  • the particular chemical moiety for RI, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade one or more of SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7.
  • the particular chemical moiety for RI, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade SIRT5 activity. In some embodiments, the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin (e.g., SIRT5) related desuccinylase activity. In some embodiments, the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin (e.g., SIRT5) related demalonylase activity.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin (e.g., SIRT5) related deglutarylase activity.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to influence multiple cellular pathways related to sirtuin activity (e.g., SIRT5) such as ammonia detoxification, fatty acid oxidation, cellular respiration, ketone body formation, tricarboxylic acid cycle (TCA), glycolysis and reactive oxygen species (ROS) metabolism.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to serve as a therapeutic for treating, preventing and/or ameliorating disorders characterized with sirtuin (e.g., SIRT5) activity (e.g., sirtuin related cancer (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer).
  • sirtuin e.g., SIRT5
  • sirtuin related cancer e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer.
  • R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
  • A is selected from the group consisting of NH, CH2, O, S, (thiourea), amide, and sulfonamide.
  • B is an aromatic ring.
  • B is a thiazole ring (e.g., E is an aromatic ring.
  • E is a benzene ring.
  • each R 2 within is independently selected from the group consisting of hydrogen, halogen, (e.g., F, Cl, Br, I), alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, halogen, aryl, heteroaryl, arylalkyl, heteroarylalkyl, nilryl, cyano, amide or sulfonamide, and triphenylphosphine (TPP) attached with linker, and/o wherein each R 2 within independently selected from the group consisting of hydrogen, halogen, CF 3 , OCH 3 , OH, NO 2 (nitryl), CN (cyano), amide (e.g.,
  • NHC(O)CH3) NHC(O)CH3
  • sulfonamide e.g., S(O2)NHCH3
  • TPP triphenylphosphine
  • linker is covalently bonded to connect two parts; the carbon atom in the linear chain can be substituted with oxygen, nitrogen, sulfur, ester, and amide.
  • linker is of following Formula (L0) : ; or an enantiomer, diastereomer, or stereoisomer thereof, wherein zl is an integer selected from 0 to 10; Z2 is an integer selected from 0 to 10; Z3 is an integer selected from 0 to 10; each X is independently absent, CH 2 , 0, S, NH, NR 13; wherein W is selected from absent, O, NH, NR 13 , -OCH 2 C(O)NH-, -CH2CH 2 C(O)NH-, -CH 2 C(O)NH- or -C(O)NH-; wherein Y is absent, O, NH, NR 13 , -OCH 2 C(O)NH-, -CH 2 CH 2 C(O)NH-, - CH 2 C(O)NH- or -C(O)NH-; and each R 13 is independently C1-C3 alkyl.
  • the linker can be substituted with an alkyl, hal
  • linker is one of the following moieties:
  • R 2 is represented by Formula (PO):
  • Formula (PO) wherein the linker is covalently bonded to connect two parts; wherein the carbon atom in the linear chain can be substituted with oxygen, nitrogen, sulfur, ester, and amide; wherein ULM represents an E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase selected from the group consisting of pomalidomide, thalidomide, lenalidomide, Von Hippel-Lindau (VHL), inhibitors of apoptosis proteins (IAP), Cereblon, and mouse double minute 2 (MDM2).
  • VHL Von Hippel-Lindau
  • IAP inhibitors of apoptosis proteins
  • MDM2 mouse double minute 2
  • R3 is hydrogen or OH.
  • prodrug is preferably carboxylic acid ester.
  • the ester group masks the negative charge on the carboxylate and thus can increase the cell permeability of the compounds. Inside the cells, the ester group can be hydrolyzed to release the negatively charged carboxylate, which can inhibit SIRT5.
  • Table I compounds shown in Table I are contemplated for Formula (1).
  • Table I additionally shows values for SIRT5 IC 50 for select compounds.
  • the invention further provides processes for preparing any of the compounds of the present invention.
  • the invention also provides the use of compounds to not only inhibit sirtuin activity but also signaling pathways dependent upon or related to sirtuins.
  • the invention also relates to the use of compounds for sensitizing cells to additional agent(s), such as agents known to be effective in the treatment of disorders related to sirtuin activity (e.g., cancer).
  • the compounds of the invention are useful for the treatment, amelioration, or prevention of disorders associated with sirtuin (e.g., SIRT5) activity (e.g., cancer), such as those responsive to sirtuin (e.g., SIRT5) activity inhibition (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer).
  • sirtuin activity e.g., cancer
  • SIRT5 activity inhibition e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer.
  • the present invention provides methods of treating, ameliorating, or preventing a disorder related to sirtuin (e.g., SIRT5) activity in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition comprising a compound encompassed within Formulas 1, 2 or 3, and/or a compound recited in Table.
  • a disorder related to sirtuin e.g., SIRT5
  • kits comprising a compound of the invention and instructions for administering the compound to an animal.
  • the kits may optionally contain other therapeutic agents, e.g., agents useful in treating disorders related to sirtuin (e.g., SIRT5) activity (e.g., cancer).
  • FIG. 1A-B (A) Structure of compound 1-2; (B) Compound 1-2 inhibited growth of Ewing sarcoma cell - A4573 and A673.
  • FIG. 2A-C (A) Structures of compound 1-3; (B) Compound 1-3 degraded protein SIRT5; (Q Compound 1-3 inhibited growth of Ewing sarcoma cell lines A4573 and A673.
  • alkyl means a saturated hydrocarbon radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms, most preferably 1 to 3 carbon atoms, that may be branched or unbranched.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, pentyl, hexyl, heptyl, octyl and the like, wherein methyl, ethyl, n-propyl and isopropyl represent specifically preferred examples.
  • cycloalkyl refers to a saturated hydrocarbon ring that is not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic or polycyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 12 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings.
  • Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl rings.
  • halo or “halogen” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo.
  • heteroatom is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
  • heteroalkyl is a saturated or unsaturated chain carbon and at least one heteroatom, wherein no two heteroatoms are adjacent Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5.
  • alkoxy (i.e.,-O-alkyl or -O-heteroalkyl) radicals are included in heteroalkyl.
  • Heteroalkyl chains may be straight or branched.
  • Preferred branched heteroalkyl have one or two branches, preferably one branch.
  • Preferred heteroalkyl are saturated.
  • Unsaturated heteroalkyl have one or more carbon-carbon double bounds and/or one or more carbon-carbon triple bounds.
  • Preferred unsaturated heteroalkyl have one or two carbon-carbon double bounds or one carbon-carbon triple bound, more preferably one double bound.
  • Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents.
  • Preferred substituted heteroalkyl are mono-, di, or tri-substituted.
  • Heteroalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof.
  • heterocycloalkyl is a saturated or unsaturated ring containing carbon atoms and from 1 to 4 (preferably 1 to 3) heteroatoms in the ring.
  • Heterocycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic or polycyclic ring systems.
  • Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (including both carbons and heteroatoms), preferably from 5 to 7 member atoms, in the ring.
  • Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems.
  • Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6- or 7- membered rings.
  • Heterocycloalkyl rings may be unsubstituted (i.e., contain hydrogen) or substituted (on either carbons or heteroatoms or both) with from 1 to 4 substituents selected from halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof.
  • Preferred heterocycloalkyl rings include, but are not limited to, any of the following:
  • aromatic rings include aromatic hydrocarbon rings and heteroaromatic rings.
  • Aromatic rings may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted aromatic rings are mono-, di, or tri-subsdtuted.
  • Aromatic rings may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof.
  • Preferred aromatic rings include, but are not limited to, the following:
  • arylalkyl or “aralkyl” alone or in combination, refers to an alkyl radical in which one hydrogen atom is replaced by an aryl radical, for example, benzyl and the like.
  • heteroarylalkyl refers to an alkyl radical in which one hydrogen atom is replaced by a heteroaryl radical.
  • composition refers to a mixture of one or more of die compounds described herein or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and/or excipients.
  • a pharmacological composition is to facilitate administration of a compound to an organism.
  • pharmaceutically acceptable salts is a cationic salt formed at any acidic (e.g., carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group.
  • linker is covalently bonded to connect two parts; the carbon atom in the linear drain can be substituted with oxygen, nitrogen, sulfur, ester, and amide.
  • linker is of following Formula (L0): or an enantiomer, diastereomer, or stereoisomer thereof, wherein zl is an integer selected from 0 to 10; Z2 is an integer selected from 0 to 10; Z3 is an integer selected from 0 to 10; each X is independently absent, CH 2 , O, S, NH, NRi3: W is selected from absent, O, NH, NRi3.
  • linker can be substituted with an alkyl, halide, phenyl, benzyl, aryl, alkylene or heterocycle group. Examples of applicable linkers include, but are not limited to, the following:
  • ULM represents a E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase selected from the group consisting of VHL, IAP, Cereblon, and mouse double minute 2 (MDM2).
  • MDM2 mouse double minute 2
  • ULM includes but is not limited to, the following: pomalldomide thalidomide lenalidomide
  • PROTACs represents proteolysis-targeting chimeras.
  • Proteolysis-targeting chimeras are heterobifunctional compounds with two recruiting ligands connected via a linker. One ligand is specific to the protein of interest (POI) while the other moiety specifically recruits an E3 ligase.
  • POI protein of interest
  • the PROTAC thus forms a ternary complex upon binding to both its E3 ligase target and the protein of interest.
  • PROTACS By hijacking the E3 ligase, PROTACS position the POI in a spatially favorable presentation to facilitate substrate poly-ubiquitination, thereby selectively knocking down levels of the targeted protein (e.g., Crews, C. M., et al., Angewandte Chemie. Int. Ed. 55, 1966-1973, 2016).
  • optical isomer e.g., a cis and/or trans isomer
  • tautomers e.g., the tautomerism of keto form and enol form
  • stereoisomer e.g., the tautomerism of keto form and enol form
  • diastereomer e.g., Hawley’s Condensed Chemical Dictionary, 11 th Ed.
  • the illustration of specific protected forms and other derivatives of the compounds of the instant invention are not intended to be limiting. The application of other useful protecting groups, salt forms, prodrugs etc., is within the ability of the skilled artisan.
  • prodrug is a form of drug that must undergo chemical conversion by metabolic processes before becoming an active, or fully active, pharmacological agent.
  • a prodrag is not active or is less active, in its ingested or absorbed or otherwise administered form.
  • a prodrag may be broken down by bacteria in the digestive system into products, at least one of which will become active as a drug.
  • it may be administered systemically, such as by intravenous injection, and subsequently be metabolized into one or more active molecules.
  • solvate is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist’s Dictionary, p. 650 (1953).
  • sirtuins are a class of nicotinamide adenine dinucleotide (NAD + )-dependent deacylases. There are seven sirtuin members encoded in mammalian genomes, SIRT1 through SIRT7.
  • SIRT5 is an inefficient deacetylase; instead it possesses very efficient desuccinylase, demalonylase, and deglutarylase activities, thereby influencing multiple cellular pathways such as ammonia detoxification, fatty acid oxidation, cellular respiration, ketone body formation, tricarboxylic acid cycle (TCA), glycolysis and reactive oxygen species (ROS) metabolism.
  • Dysregulation of SIRT5 is found in several human diseases, especially cancer. It was found that SIRT5 depletion in specific cancer types (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, neuroblastoma) induces rapid cell death.
  • Such experiments involved a screening an in-house library of compounds using a thermal shift assay and identified a novel class of 2-hydroxybenzoic acid derivatives as SIRT5 inhibitors. Such experiments also involved a successful development of PROTACs selectively inducing the degradation of SIRT5 protein that mainly resides in the mitochondrial matrix.
  • These inhibitors and degraders are contemplated to useful in the treatment of disorders associated with sirtuins, for example, cancer (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, neuroblastoma, non-small cell lung cancer).
  • the present invention relates to a new class of small-molecules having a 2-hydroxybenzoic acid structure which function as sirtuin (e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7) inhibitors and/or degraders which function as effective therapeutic agents for treating, ameliorating, and preventing disorders associated with sirtuin activity (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer).
  • this invention also relates to a new class of proteolysis- targeting chimeras (PROTACs) (as defined herein) which function as sirtuin inhibitors and/or degraders within cancer and/or immune cells.
  • PROTACs proteolysis- targeting chimeras
  • Pharmaceutical compositions comprising said compounds are also within the scope of the present invention.
  • Formulas (1), (2), and (3) are not limited to a particular chemical moiety for Rl, R2, R3, A, B and E.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin activity (e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7).
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade one or more of SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade SIRT5 activity. In some embodiments, the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin (e.g., SIRT5) related desuccinylase activity. In some embodiments, the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin (e.g., SIRT5) related demalonylase activity.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to inhibit and/or degrade sirtuin (e.g., SIRT5) related deglutarylase activity.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to influence multiple cellular pathways related to sirtuin activity (e.g., SIRT5) such as ammonia detoxification, fatty acid oxidation, cellular respiration, ketone body formation, tricarboxylic acid cycle (TCA), glycolysis and reactive oxygen species (ROS) metabolism.
  • the particular chemical moiety for Rl, R2, R3, A, B and E independently include any chemical moiety that permits the resulting compound to serve as a therapeutic for treating, preventing and/or ameliorating disorders characterized with sirtuin (e.g., S1RT5) activity (e.g., sirtuin related cancer (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer).
  • sirtuin e.g., S1RT5
  • sirtuin related cancer e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer.
  • R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
  • A is selected from the group consisting of NH, CH2, 0, S, (thiourea), amide, and sulfonamide.
  • B is an aromatic ring. In some embodiments, B is a thiazole ring (e.g., In some embodiments, E is an aromatic ring. In some embodiments, E is a benzene ring.
  • each R 2 within is independently selected from the group consisting of hydrogen, halogen, (e.g., F, Cl, Br, I), alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, halogen, aryl, heteroaryl, arylalkyl, heteroarylalkyl, nilryl, cyano, amide or sulfonamide, , and triphenylphosphine (TPP) attached with linker, and/or wherein each R 2 within independently selected from the group consisting of hydrogen, halogen, CF3, OCH 3 , OH, NO 2 (nitryl), CN (cyano), amide (e.g.,
  • NHC(O)CH3) NHC(O)CH3
  • sulfonamide e.g., S(O2)NHCH3
  • TPP triphenylphosphine
  • linker is covalently bonded to connect two parts; the carbon atom in the linear chain can be substituted with oxygen, nitrogen, sulfur, ester, and amide.
  • linker is of following Formula (L0) :
  • each X is independently absent, CH 2 , 0, S, NH, NR 13; wherein W is selected from absent, O, NH, NR 13 , -OCH 2 C(O)NH-, -CH2CH 2 C(O)NH-, -CH 2 C(O)NH- or -C(O)NH-; wherein Y is absent, O, NH, NR 13 , -OCH 2 C(O)NH-, -CH 2 CH 2 C(O)NH-, - CH 2 C(O)NH- or -C(O)NH-; and each R 13 is independently C1-C3 alkyl.
  • the linker can be substituted with an alkyl, halide, phenyl, benzyl, aryl, al
  • linker is one of the following moieties:
  • Formula (PO) wherein the linker is covalently bonded to connect two parts; wherein the carbon atom in the linear chain can be substituted with oxygen, nitrogen, sulfur, ester, and amide; wherein ULM represents an E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase selected from the group consisting of pomalidomide, thalidomide, lenalidomide, Von Hippel-Lindau (VHL), inhibitors of apoptosis proteins (IAP), Cereblon, and mouse double minute 2 (MDM2).
  • VHL Von Hippel-Lindau
  • IAP inhibitors of apoptosis proteins
  • MDM2 mouse double minute 2
  • R3 is hydrogen or OH.
  • prodrug is preferably carboxylic acid ester.
  • the ester group masks the negative charge on the carboxylate and thus can increase the cell permeability of the compounds. Inside the cells, the ester group can be hydrolyzed to release the negatively charged carboxylate, which can inhibit SIRT5.
  • Table I compounds shown in Table I are contemplated for Formula (1).
  • Table I additionally shows values for SIRT5 IC 50 for select compounds.
  • compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological conditions and/or disease states in an animal (e.g., a mammalian patient including, but not limited to, humans and veterinary animals).
  • an animal e.g., a mammalian patient including, but not limited to, humans and veterinary animals.
  • various diseases and pathologies are amenable to treatment or prophylaxis using the present methods and compositions.
  • a non-limiting exemplary list of these diseases and conditions includes, but is not limited to, cancer associated with sirtuin (e.g., SIRT5) activity (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer).
  • a non-limiting exemplary list of cancers include, but are not limited to, pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia,
  • Some embodiments of the present invention provide methods for administering an effective amount of a compound of the invention and at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosis-modulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, and/or radiotherapies).
  • additional therapeutic agent including, but not limited to, chemotherapeutic antineoplastics, apoptosis-modulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory agents
  • therapeutic technique e.g., surgical intervention, and/or radiotherapies.
  • anticancer agents are contemplated for use in the methods of the present invention. Indeed, the present invention contemplates, but is not limited to, administration of numerous anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., anti-sense, ribozymes, siRNA); polypeptides (e.g., enzymes and antibodies); biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins), toxins; radionuclides; biological response modifiers (e.g., interferons (e.g., IFN- ⁇ ) and interleukins (e.g., IL-2)); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-rednoic acid); gene therapy
  • anticancer agents comprise agents that induce or stimulate apoptosis.
  • Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, UV); tumor necrosis factor (TNF)-related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2); kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitor, vascular growth factor receptor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) kinase inhibitor, platelet-derived growth factor receptor (PDGFR) kinase inhibitor, and Bcr-Abl kinase inhibitors (such as GLEEVEC)); antisense molecules; antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN, and AVASTIN); anti-be
  • compositions and methods of the present invention provide a compound of the invention and at least one anti-hypeiproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and/or animal derived compounds).
  • at least one anti-hypeiproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and/or animal derived compounds).
  • Alkylating agents suitable for use in the present compositions and methods include, but are not limited to: 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-saicolysin); and chlorambucil); 2) ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa); 3) alkyl sulfonates (e.g., busulfan); 4) nitrosoureas (e.g., carmustine (BCNU); lomustine (CCNU); semustine (methyl- CCNU); and streptozocin (streptozotocin)); and 5) triazenes (e.g., dacarbazine (DTIC; dimethyltriazenoimid-azolecarboxamide).
  • nitrogen mustards e.g., mechlorethamine, cyclophosphamide
  • antimetabolites suitable for use in the present compositions and methods include, but are not limited to: 1) folic acid analogs (e.g., methotrexate (amethopterin)); 2) pyrimidine analogs (e.g., fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorode-oxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; TG), and pentostatin (2’-deoxycoformycin)).
  • folic acid analogs e.g., methotrexate (amethopterin)
  • pyrimidine analogs e.g., fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorode-oxyuridine; FudR), and cytarabine
  • chemotherapeutic agents suitable for use in the compositions and methods of the present invention include, but are not limited to: 1) vinca alkaloids (e.g., vinblastine (VLB), vincristine); 2) epipodophyllotoxins (e.g., etoposide and teniposide); 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)); 4) enzymes (e.g., L-asparaginase); 5) biological response modifiers (e.g., interferon-alfa); 6) platinum coordinating complexes (e.g., cisplatin (cis-DDP) and carboplatin); 7) anthracenediones (e.g., mitoxantrone); 8) substitute
  • any oncolytic agent that is routinely used in a cancer therapy context finds use in the compositions and methods of the present invention.
  • the U.S. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. International counterpart agencies to the U.S.F.D.A. maintain similar formularies.
  • Table 2 provides a list of exemplary antineoplastic agents approved for use in the U.S. Those skilled in the art will appreciate that the “product labels” required on all U.S. approved chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents.
  • Anticancer agents further include compounds which have been identified to have anticancer activity. Examples include, but are not limited to, 3-AP, 12-0- tetradecanoylphorbol-13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI- PEG 20, AE-941, AG-013736, AGROIOO, alanosine, AMG 706, antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BG00001, bicalutamide, BMS 247550, bortezomib, bryostatin-1, buserelin, calcitriol, CCI-779, CDB-2914, cefixime, cetuximab, CG0070, cilengitide, clofarabine, combretastat
  • the present invention provides methods for administering a compound of the invention with radiation therapy.
  • the invention is not limited by the types, amounts, or delivery and administration systems used to deliver the therapeutic dose of radiation to an animal.
  • the animal may receive photon radiotherapy, particle beam radiation therapy, other types of radiotherapies, and combinations thereof.
  • the radiation is delivered to the animal using a linear accelerator.
  • the radiation is delivered using a gamma knife.
  • the source of radiation can be external or internal to the animal.
  • External radiation therapy is most common and involves directing a beam of high-energy radiation to a tumor site through the skin using, for instance, a linear accelerator. While the beam of radiation is localized to the tumor site, it is nearly impossible to avoid exposure of normal, healthy tissue. However, external radiation is usually well tolerated by animals.
  • Internal radiation therapy involves implanting a radiation-emitting source, such as beads, wires, pellets, capsules, particles, and the like, inside the body at or near the tumor site including the use of delivery systems that specifically target cancer cells (e.g., using particles attached to cancer cell binding ligands). Such implants can be removed following treatment, or left in the body inactive.
  • Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmunotherapy, and the like.
  • the animal may optionally receive radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (ludR), nitroimidazole, 5- substituted-4-nitroimidazoles, 2H-isoindolediones, [[(2-bromoethyl)-amino]methyl]-nitro- 1H-imidazole-l-ethanol, nitroaniline derivatives, DNA-affinic hypoxia selective cytotoxins, halogenated DNA ligand, 1,2,4 benzotriazine oxides, 2-nitroimidazole derivatives, fluorine- containing nitroazole derivatives, benzamide, nicotinamide, acridine-intercalator, 5- thiotretrazole derivative, 3-nitro-l,2,4-triazole, 4,5-dinitroimidazole derivative, hydroxylated texaphrins, c
  • Radiotherapy any type of radiation can be administered to an animal, so long as the dose of radiation is tolerated by the animal without unacceptable negative side-effects.
  • Suitable types of radiotherapy include, for example, ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) or particle beam radiation therapy (e.g. , high linear energy radiation).
  • Ionizing radiation is defined as radiation comprising particles or photons that have sufficient energy to produce ionization, i.e., gain or loss of electrons (as described in, for example, U.S. 5,770,581 incorporated herein by reference in its entirety).
  • the effects of radiation can be at least partially controlled by the clinician.
  • the dose of radiation is fractionated for maximal target cell exposure and reduced toxicity.
  • the total dose of radiation administered to an animal is about .01 Gray (Gy) to about 100 Gy.
  • about 10 Gy to about 65 Gy e.g., about 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy
  • a complete dose of radiation can be administered over the course of one day
  • the total dose is ideally fractionated and administered over several days.
  • radiotherapy is administered over the course of at least about 3 days, e.g., at least 5, 7, 10, 14, 17, 21, 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1-8 weeks).
  • a daily dose of radiation will comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy), or 1-2 Gy (e.g., 1.5-2 Gy).
  • the daily dose of radiation should be sufficient to induce destruction of the targeted cells.
  • radiation is not administered every day, thereby allowing the animal to rest and the effects of the therapy to be realized.
  • radiation desirably is administered on 5 consecutive days, and not administered on 2 days, for each week of treatment, thereby allowing 2 days of rest per week.
  • radiation can be administered 1 day/week, 2 days/week, 3 days/week, 4 days/week, 5 days/week, 6 days/week, or all 7 days/week, depending on the animal’s responsiveness and any potential side effects.
  • Radiation therapy can be initiated at any time in the therapeutic period. In one embodiment, radiation is initiated in week 1 or week 2, and is administered for the remaining duration of the therapeutic period. For example, radiation is administered in weeks 1-6 or in weeks 2-6 of a therapeutic period comprising 6 weeks for treating, for instance, a solid tumor. Alternatively, radiation is administered in weeks 1-5 or weeks 2-5 of a therapeutic period comprising 5 weeks.
  • These exemplary radiotherapy administration schedules are not intended, however, to limit the present invention.
  • Antimicrobial therapeutic agents may also be used as therapeutic agents in the present invention. Any agent that can kill, inhibit, or otherwise attenuate the function of microbial organisms may be used, as well as any agent contemplated to have such activities.
  • Antimicrobial agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g., defensins), antisense nucleic acids, membrane disruptive agents and the like, used alone or in combination. Indeed, any type of antibiotic may be used including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like.
  • a compound of the invention and one or more therapeutic agents or anticancer agents are administered to an animal under one or more of the following conditions: at different periodicities, at different durations, at different concentrations, by different administration routes, etc.
  • the compound is administered prior to the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of the therapeutic or anticancer agent.
  • the compound is administered after the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the anticancer agent.
  • the compound and the therapeutic or anticancer agent are administered concurrently but on different schedules, e.g., the compound is administered daily while the therapeutic or anticancer agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks.
  • the compound is administered once a week while the therapeutic or anticancer agent is administered daily, once a week, once every two weeks, once every three weeks, or once every four weeks.
  • compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis. In one embodiment, about 0.01 to about 25 mg/kg is orally administered to treat, ameliorate, or prevent such disorders.
  • the dose is generally about one-half of the oral dose.
  • a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, or from about 0.01 to about 5 mg/kg.
  • the unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of the compound.
  • the unit dose may be administered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound or its solvates.
  • the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In a one embodiment, the compound is present at a concentration of about 0.07-1.0 mg/ml, for example, about 0.1-0.5 mg/ml, and in one embodiment, about 0.4 mg/ml.
  • the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the excipient.
  • compositions of the invention may be administered to any patient which may experience the beneficial effects of the compounds of the invention.
  • mammals e.g., humans, although the invention is not intended to be so limited.
  • Other patients include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like).
  • the compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above- mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flowregulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the topical compositions of this invention are formulated in one embodiment as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12).
  • the carriers may be those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U.S. Pat Nos. 3,989,816 and 4,444,762; each herein incorporated by reference in its entirety.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool.
  • a vegetable oil such as almond oil
  • a typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight.
  • Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.
  • reaction conditions (a) HC1, H 2 O, rt; (b) aqueous ammonia, rt;(c) N-(4-(2- bromoacetyl)phenyl)acetamide , EtOH, reflux.
  • reaction conditions (a) H2SO4, EtOH, reflux; (b) acetylchloride, DMF, 0 °C to rt; (c) HATU , DIPEA, DMF, rt; (d) TFA , DCM, rt; (e) 2-((2-(2,6-dioxopiperidin-3-yl)
  • reaction conditions (a) pyridine, 60 °C.
  • reaction conditions (a) CaCO 3 , DCM, H 2 O, reflux; (b) pyridine, 60 °C.
  • Ethyl 2-hydroxy-4-isothiocyanatobenzoate (2-13) A mixture of thiophosgene (228 ⁇ L, 3 mmol), CaCO 3 (175 mg, 1.75 mmol), DCM (2 mL) and H 2 O (4 mL) was stirred at rt, then a solution of amine 2-12 (181 mg, 1 mmol) in DCM (2 mL) was added dropwise. The reaction mixture was refluxed for 48 h.
  • reaction conditions (a) CaCCb, DCM, H 2 O, rt; (b) pyridine, 60 °C.
  • SIRT5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806-809. Gaspar, N., Hawkins, D.S., Dirksen, U., Lewis, I.J., Ferrari, S., Le Deley, M.C., Kovar, H., Grimer, R., Whelan, J., Claude, L., et al. (2015). Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. J Clin Oncol 33, 3036-3046.
  • SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem Biophys Res Commun 441, 191-195.
  • SIRT5 facilitates cancer cell growth and drag resistance in non-small cell lung cancer.
  • Tumour biology the journal of the International Society for Oncodevelopmental Biology and Medicine.
  • SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137, 560-570.
  • SIRT5 Regulates both Cytosolic and Mitochondrial Protein Malonylation with Glycolysis as a Major Target. Mol Cell 59, 321-332.
  • SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 50, 919-930.
  • SIRT5 Regulates the Mitochondrial Lysine Succinylome and Metabolic Networks. Cell Metab 18, 920-933.
  • Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 19, 605-617.
  • Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Rep 4, 842-851.
  • SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense.
  • SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc Natl Acad Sci U S A.
  • SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

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Abstract

Cette invention se rapporte au domaine de la chimie médicale. En particulier, l'invention concerne une nouvelle classe de petites molécules ayant une structure acide 2-hydroxybenzoïque qui jouent le rôle d'inhibiteurs et/ou d'agents de dégradation de la sirtuine (par exemple, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7) pouvant faire fonction d'agents thérapeutiques efficaces pour traiter, atténuer et prévenir des troubles associés à l'activité de la sirtuine (par exemple, un mélanome, un sarcome d'Ewing, une tumeur maligne des gaines nerveuses périphériques, un cancer du poumon non à petites cellules). De plus, la présente invention concerne également une nouvelle classe de chimères ciblant la protéolyse (PROTAC) (telles que définies dans la description) qui jouent le rôle d'inhibiteurs et/ou d'agents de dégradation de la sirtuine dans des cellules cancéreuses et/ou immunitaires. La présente invention concerne également des compositions pharmaceutiques comprenant lesdits composés.
PCT/US2023/020366 2022-04-29 2023-04-28 Petites molécules inhibitrices de la sirtuine et leurs utilisations WO2024005905A2 (fr)

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Publication number Priority date Publication date Assignee Title
TW200916472A (en) * 2007-06-20 2009-04-16 Sirtris Pharmaceuticals Inc Sirtuin modulating compounds
US9315449B2 (en) * 2008-05-15 2016-04-19 Duke University Substituted pyrazoles as heat shock transcription factor activators
ITMI20130647A1 (it) * 2013-04-19 2014-10-20 Univ Bologna Alma Mater Composti con attività inibente sulle sirtuine

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